Ergotamines such as, for example, dihydroergotamine mesylate are well established therapeutic agents for the treatment of migraine. More recently, a number of highly selective agents for the treatment of migraine which have high 5-HT1D:5-HT1B binding ratios have been prepared, such as, for example, the alkyltryptamine derivatives (125-fold selectivity, Slassi, Bioorg. Med. Chem. Lett. 10: 1707-1709, (2000)), the indole series (300-fold selectivity, Castro, J. Med. Chem. 41: 2667 (1998)) and from the non-indole series (>6000 fold selectivity, Ennis, J. Med. Chem. 41: 2180 (1998)). However, strong agonism of 5-HT1B by migraine therapeutics such as, for example, sumatriptan (Phebus, Cephalalgia 17: 245 (1997)) frequently leads to adverse cardiovascular effects due to excessive vasoconstriction. Accordingly, an effective migraine agent should be selective for the 5-HT1D receptor over the 5-HT1B receptor, but with moderate agonism of the 5-HT1B receptor to minimize non-cranial vasoconstriction. Antagonism of adrenergic receptors, such as, for example, alpha1A, alpha1D, alpha2A, alpha2B and alpha2C by migraine therapeutics can reduce vasoconstriction caused by strong 5-HT1B agonism.
Agonism of dopamine receptors is highly unfavorable for anti-migraine compounds since nausea is a classic dopaminergic (activation of dopamine receptors) symptom, which is already an indication of migraine itself. Yet another problem with many migraine therapeutics and especially ergoline derivatives is undesirable agonism of 5-HT2B receptors which is associated with cardiac and non-cardiac fibrosis, including cardiovascular valvulopathy (Rothman, Circulation 102: 2836 (2000)). Conversely, antagonism of 5-HT2B receptors may offer therapeutic advantages in the treatment and/or prevention of migraine (Schaerlinger, Br. J. Pharmacol. 140(2): 277-84, (2003)).
Accordingly, there is a continuing need for less toxic ergoline derivatives to treat and/or prevent disorders such as, for example, migraine, which selectively agonize 5-HT1D receptors over 5-HT1B receptors with moderated 5-HT1B receptor agonism, have low dopamine receptor agonism and are 5-HT2B and adrenergic receptor antagonists.